EFSA/GMO/578 – part of the Minutes 55th Plenary Meeting of the GMO Panel Adopted part of the minutes1 of the 55th plenary meeting of the Scientific Panel on Genetically Modified Organisms held on 27-28 January 2010 to be published at http://www.efsa.europa.eu/en/events/event/gmo100127.htm
GMO Panel deliberations on the paper by de Vendômois et al. (2009, A Comparison of the Effects of Three GM Corn Varieties on Mammalian Health, International Journal of Biological Sciences, 5: 706-726)
The EFSA GMO Panel has considered the paper by de Vendômois et al. (2009, A Comparison of the Effects of Three GM Corn Varieties on Mammalian Health, International Journal of Biological Sciences, 5: 706-726), a statistical reanalysis of data from three 90-day rat feeding studies already assessed by the GMO Panel (EFSA, 2003a,b; EFSA 2004a,b; EFSA 2009b,c). The GMO Panel concludes that the authors’ claims, regarding new side effects indicating kidney and liver toxicity, are not supported by the data provided in their paper. There is no new information that would lead it to reconsider its previous opinions on the three maize events MON810, MON863 and NK603, which concluded that there were no indications of adverse effects for human, animal health and the environment.
The GMO Panel notes that several of its fundamental statistical criticisms (EFSA, 2007a,b) of the authors’ earlier study (Seralini et al., 2007) of maize MON863 are also applicable to the new paper by de Vendômois et al. In the GMO Panel’s extensive evaluation of Seralini et al. (2007), reasons for the apparent excess of significant differences found for MON863 (8%) were given and it was shown that this raised no safety concerns. The percentage of variables tested reported by de Vendômois et al. that were significant for NK603 (9%) and MON810 (6%) were of similar magnitude to that for MON863. The GMO Panel considers that de Vendômois et al.: (1) make erroneous statements concerning the use of reference varieties to provide estimates of variability that allow equivalence testing to place statistically significant results into biological context as advocated by EFSA (2008, 2009a); (2) do not use the available information concerning normal background variability between animals fed with different diets, to place observed differences into biological context; (3) do not present results using their False Discovery Rate methodology in a meaningful way; (4) give no evidence to relate wellknown gender differences in response to diet to claims of effects due to the respective GMOs; (5) estimate statistical power based on inappropriate analyses and magnitudes of difference.
The significant differences highlighted by de Vendômois et al. have all been considered previously by the GMO Panel in its previous opinions on the three maize events MON810, MON863 and NK603. The study by de Vendômois et al. provides no new evidence of toxic effects. The approach used by de Vendômois et al. does not allow a proper assessment of the differences claimed between the GMOs and their respective counterparts for their toxicological relevance because: (1) results are presented exclusively in the form of percentage differences for each variable, rather than in their actual measured units; (2) the calculated values of the toxicological parameters tested are not related to the normal range for the species concerned; (3) the calculated values of the toxicological parameters tested are not compared with ranges of variation found in test animals fed with diets containing different reference varieties; (4) the statistically significant differences did not show consistency patterns over endpoint variables and doses; (5) the inconsistencies between the purely statistical arguments of de Vendômois et al., and the results for these three animal feeding studies which relate to organ pathology, histopathology and histochemistry, are not addressed. Regarding claims made by de Vendômois et al. concerning the inadequacy of the experimental design of these three animal feeding studies, the GMO Panel notes that they were all carried out to agreed internationally-defined standards consistent with OECD protocols.
1 The complete minutes will be adopted at the 56th plenary meeting (10-11 March 2010) and will be published shortly afterwards. EFSA/GMO/578 – part of the Minutes 55th Plenary Meeting of the GMO Panel References
EFSA, 2003a. Opinion of the Scientific Panel on genetically modified organisms (GMO) on a request from the Commission related to the safety of foods and food ingredients derived from herbicidetolerant genetically modified maize NK603, for which a request for placing on the market was submitted under Article 4 of the Novel Food Regulation (EC) No 258/97 by Monsanto. http://www.efsa.europa.eu/en/scdocs/scdoc/9.htm
EFSA, 2003b. Opinion of the Scientific Panel on genetically modified organisms (GMO) on a request from the Commission related to the Notification (Reference CE/ES/00/01) for the placing on the market of herbicide-tolerant genetically modified maize NK603, for import and processing, under Part C of Directive 2001/18/EC from Monsanto. http://www.efsa.europa.eu/en/scdocs/scdoc/10.htm
EFSA, 2004a. Opinion of the Scientific Panel on genetically modified organisms (GMO) on a request from the Commission related to the Notification (Reference C/DE/02/9) for the placing on the market of insect-protected genetically modified maize MON 863 and MON 863 x MON 810, for import and processing, under Part C of Directive 2001/18/EC from Monsanto. http://www.efsa.europa.eu/en/scdocs/scdoc/49.htm
EFSA, 2004b. Opinion of the Scientific Panel on genetically modified organisms (GMO) on a request from the Commission related to the safety of foods and food ingredients derived from insectprotected genetically modified maize MON 863 and MON 863 x MON 810, for which a request for placing on the market was submitted under Article 4 of the Novel Food Regulation (EC) No 258/97 by Monsanto. http://www.efsa.europa.eu/en/scdocs/scdoc/50.htm
EFSA, 2007a. EFSA review of statistical analyses conducted for the assessment of the MON 863 90- day rat feeding study. http://www.efsa.europa.eu/en/scdocs/scdoc/19r.htm EFSA, 2007b. Statement on the analysis of data from a 90-day rat feeding study with MON 863 maize by the Scientific Panel on genetically modified organisms (GMO). http://www.efsa.europa.eu/en/scdocs/scdoc/753.htm
EFSA, 2008. Updated guidance document for the risk assessment of genetically modified plants and derived food and feed. Annex A. http://www.efsa.europa.eu/en/scdocs/scdoc/293r.htm EFSA, 2009a. Statistical considerations for the safety evaluation of GMOs. http://www.efsa.europa.eu/en/scdocs/scdoc/1250.htm
EFSA, 2009b. Applications (references EFSA-GMO-NL-2005-22, EFSA-GMO-RX-NK603) for the placing on the market of the genetically modified glyphosate tolerant maize NK603 for cultivation, food and feed uses, import and processing and for renewal of the authorisation of maize NK603 as existing products, both under Regulation (EC) No 1829/2003 from Monsanto. http://www.efsa.europa.eu/en/scdocs/scdoc/1137.htm
EFSA, 2009c. Applications (EFSA-GMO-RX-MON810) for renewal of authorisation for the continued marketing of (1) existing food and food ingredients produced from genetically modified insect resistant maize MON810; (2) feed consisting of and/or containing maize MON810, including the use of seed for cultivation; and of (3) food and feed additives, and feed materials produced from maize MON810, all under Regulation (EC) No 1829/2003 from Monsanto. http://www.efsa.europa.eu/en/scdocs/scdoc/1149.htm
Seralini, G.E., Cellier D., de Vendômois J.S. 2007. New analysis of a rat feeding study with a genetically modified maize reveals signs of hepatorenal toxicity. Arch. Environ. Contam. Toxicol., 52: 596-602. EFSA/GMO/578 – part of the Minutes 55th Plenary Meeting of the GMO Panel
GMO Panel risk assessment of an updated bioinformatic analysis of maize event NK603
The EFSA GMO Panel discussed a comment by Austria on the bioinformatic data evaluated during the assessment of maize event NK603. Regarding the bioinformatic analysis of the genomic flanking regions in maize event NK603, the GMO Panel is aware of data submitted in the context of application for a triple hybrid containing event NK603, EFSA/GMO/NL/2009/65, (Tu and Silvanovich, 2009) using the same query sequence and BLAST search parameters as in the study performed for the analysis of the single event NK603 in application EFSA/GMO/NL/2005/22 (McClain and Silvanovich, 2008). As opposed to the data in McClain and Silvanovich (2008) that report no hits, results in Tu and Silvanovich (2009) indicate the existence of several homologous nucleotide sequences when a blastn analysis is performed on ESTs and non-redundant nucleotide databases. The difference between the two reports might be explained (i) by the use databases which differ from one another, not only by the dates of release, but also from the nature of the deposited sequences: “GenBank CDNA nucleotide database” in McClain and Silvanovich (2008) and “GenBank EST and non-redundant nucleotide databases” in Tu and Silvanovich (2009) ; (ii) by the used algorithms which were “publicly available BLAST algorithms” in the first study and “publicly available BLAST algorithms + algorithms downloaded from the National Center for Biotechnology Information (NCBI)” in the latter. Owing to the progress in bioinformatic tools and databases available, the importance of these analyses in the risk assessment has increased and therefore, currently, the GMO Panel requests a more extended bioinformatic analysis which includes a more detailed description of the versions and characteristics of the databases used. The results of Tu and Silvanovich (2009) are in agreement with the analysis of the Austrian experts and point to the existence of several homologous nucleotide sequences when a blastn analysis is performed on ESTs and non-redundant nucleotide databases. In order to evaluate the relevance of these matches and whether they may indicate the interruption of endogenous protein-coding genes raising possible safety concerns, the following observations must be taken into account: • Although the total length of the query sequence corresponding to the re-constructed insertion site is 808 bp, the length of the nucleotide regions matching database entries is always less than 195 bp; • The blastn analysis identified a homologous database entry corresponding to a gene sequence coding for the Zea mays P2 protein, a myb-related transcription factor (Zhang et al. 2000, The Plant Cell, 12:2311); however, the aligned interval is limited to 109 bp of the query sequence and the alignment is located outside the protein-coding part of the P2 gene sequence deposited in GenBank; this is in line with the blastx analysis which failed to identify any known protein from maize. • The blastx analysis failed to identify any known polypeptide from Zea mays and the top alignment only displays 23% identity in a window of 95 amino acids with a hypothetical protein from rice (E-Score of 0.33). Altogether, these results are not indicative of the interruption of any known endogenous proteincoding sequences and do not raise a safety concern. This conclusion is in line with the observed agronomic and compositional equivalence between NK603 maize and its conventional counterparts.